Génétique statistique

Springer
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Stephan Morgenthaler

Génétique statistique
Stephan Morgenthaler
EPFL FSB IMA
Station 8 - Bât. MA
CH-1015 Lausanne
Suisse
stephan.morgenthaler@epfl.ch

ISBN : 978-2-287-33910-3 Springer Paris Berlin Heidelberg New York

© Springer-Verlag France, Paris, 2008

Imprimé en France

Springer-Verlag France est membre du groupe Springer Science + Business Media

Cet ouvrage est soumis au copyright. Tous droits réservés, notamment la reproduction et la représentation la
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quelque procédé que ce soit est sanctionnée par la loi pénale sur le copyright.
L’utilisation dans cet ouvrage de désignations, dénominations commerciales, marques de fabrique, etc. même
sans spécification ne signifie pas que ces termes soient libres de la législation sur les marques de fabrique et la
protection des marques et qu’ils puissent être utilisés par chacun.
La maison d’édition décline toute responsabilité quant à l’exactitude des indications de dosage et des modes
d’emploi. Dans chaque cas, il incombe à l’usager de vérifier les informations données par comparaison à la
littérature existante.

Maquette de couverture : Jean-François Montmarché

 Collection
Statistique et probabilités appliquées
dirigée par Yadolah Dodge
Professeur Honoraire
Université de Neuchâtel
Suisse
yadolah.dodge@unine.ch

Comité éditorial :
Christian Genest Stephan Morgenthaler
Département de Mathématiques École Polytechnique Fédérale
et de statistique de Lausanne
Université Laval Département des Mathématiques
Québec GIK 7P4 1015 Lausanne
Canada Suisse

Marc Hallin Gilbert Saporta

Université libre de Bruxelles Conservatoire national
Campus de la Plaine CP 210 des arts et métiers
1050 Bruxelles 292, rue Saint-Martin
Belgique 75141 Paris Cedex 3
France
Ludovic Lebart
École Nationale Supérieure
des Télécommunications
46, rue Barrault
75634 Paris Cedex 13
France

Dans la même collection :

– Statistique. La théorie et ses applications
Michel Lejeune, avril 2004
– Le choix bayésien. Principes et pratique
Christian P. Robert, novembre 2005
– Maîtriser l’aléatoire. Exercices résolus de probabilités et statistique
Eva Cantoni, Philippe Huber, Elvezio Ronchetti, novembre 2006
– Régression. Théorie et applications
Pierre-André Cornillon, Éric Matzner-Løber, janvier 2007
– Le raisonnement bayésien. Modélisation et inférence
Éric Parent, Jacques Bernier, juillet 2007
– Premiers pas en simulation
Yadolah Dodge, Giuseppe Melfi, juin 2008
Avant-propos
Ce court recueil procède à une revue de diverses méthodes statistiques ap-
plicables à la génétique. Cette seconde science nous permet, mieux que nulle
autre, de faire connaissance de la pensée probabiliste. Dans l'histoire de la sta-
tistique, la génétique a souvent été à l'origine d'idées nouvelles importantes.
Nous livrons ici aux lecteurs dotés d'une formation mathématique quelques
exemples tirés de cette discipline biologique dont les concepts sont dénis au
fur et à mesure de leur introduction. Aucune connaissance biologique préalable
n'est donc nécessaire à la lecture de cet ouvrage.
Les lecteurs biologistes pourront eux aussi découvrir des modèles statis-
tiques dans un contexte familier, mais il leur faudra posséder un certain niveau
de connaissances mathématiques, ou faire preuve d'une réelle assiduité.
Les questions traitées dans les pages qui suivent constituent une sélection
personnelle et ne prétendent pas à l'exhaustivité. Nous avons notamment laissé
de côté l'analyse des données d'expressions géniques ( microarray ). De nom-
breux livres récents expliquent ce sujet de manière détaillée.
Cet ouvrage se fonde sur un cours de master (troisième ou quatrième année
universitaire) que j'ai donné plusieurs fois à l'École polytechnique fédérale de
Lausanne et à des étudiants en mathématiques, en informatique et en bio-
informatique.
Les exercices à la n des chapitres ont été élaborés par Andrei Zenide,
Sandro Gsteiger, Sahar Hosseinian et Jean-Marc Nicoletti.

Lausanne, le 15 avril 2008

Stephan Morgenthaler



Avant-propos vii
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(Cρ1 /(ρ2 + Cρ1 ) 1 − e−∆x + e−∆x
Sclone (x) =
(C/(C + 1) (1 − e−∆x ) + e−∆x




0<∆= (β − δ)2 + 4rβδ, −1 < C = −(ρ2 + (1 − r)β)/(ρ1 + (1 − r)β),

ρ1 = (−β − δ + ∆)/2, ρ2 = (−β − δ − ∆)/2.

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 x

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 dx  dx

o(dx) o(dx)
+ δ+ − (β + δ) + Sclone (x − dx).
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5     
 
dx → 0  
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−w′′ (x) (w′ (x))2 w′ (x)2 (β + δ)w′ (x)

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−B1 ρ1 exp(ρ1 x) − B2 ρ2 exp(ρ2 x)
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! 
 
r (

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= ,
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Y C = B1 /B2  ! 








 
 
x → 0

 x → ∞ !    

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2  


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! 

x → ∞ 
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r





  


 
 
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0

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λinit (kt/K) t/K + o(1/K).
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1.00

β=8.15,δδ=8.00
0.98
0.96
0.94

β=1.15,δδ=1.00
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β=9.2,δδ=8.0
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0 10 20 30 40 50 60 70

a^ge x de l'expansion clonale

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k=1
   
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k=1

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t
− λinit (u) (1 − Sclone (t − u)) du ,
0



   


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t
d d
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M  

 

  


t
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0

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Y     
 
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Indication :  
   
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0 2000 4000 6000 8000 10000

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µ
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ν−
 
  
 
 
p+ (t + 1) = (1 − µ)p+ (t) + (1 − p+ (t))ν.

!
t → ∞ 

  


 
  

p∞ ∞ ∞
+ = (1 − µ) p+ + (1 − p+ )ν

p∞
+ (1 − 1 + µ + ν) = ν
ν
p∞
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ν+µ
43 , 


[ 
   



 

 

  
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(p+ (t + 1) − p∞ ∞
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−  p− (t) 
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P++ (t) = (1 − p− (t))2
 P+− (t) = 2p− (t) (1 − p− (t)) !
     #

−−   
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  8 

   


    
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(1 − p− (t))2 1 − p− (t)
=
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2p− (t)(1 − p− (t)) 2p− (t)

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A


1 − p− (t) p− (t) p− (t) µ + p− (t)
p− (t + 1) = µ · + + = .
1 + p− (t) 1 + p− (t) 1 + p− (t) 1 + p− (t)

! 
  
p∞
− 
 

µ + p∞
−  2
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!
  

 
 
   
   




 
   
 

  
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PAA (t) = p2A (t) PAA (t + 1) = p2A (t) wAA /w̄(t)

PAa (t) = 2pA (t) pa (t) −→ PAa (t + 1) = 2pA (t) pa (t) wAa /w̄(t)
Paa (t) = p2a (t) Paa (t + 1) = p2a (t) waa /w̄(t)

  t   t + 1

8 
   
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w̄(t) = p2A (t) wAA + 2pA (t) pa (t) wAa + p2a (t) waa ,

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pA (t + 1) = p2A (t) wAA /w̄(t) + pA (t) pa (t) wAa /w̄(t) , $;0'



∆pA (t + 1) = pA (t + 1) − pA (t)
p2A (t) wAA − pA (t) w̄(t) + pA (t) pa (t) wAa
=
w̄(t)
2
p (t)pa (t) wAA − 2pA (t)pa (t) wAa + pA (t) pa (t) wAa − pA (t) p2a (t) waa
2
= A
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pA (t) pa (t) [pA (t)(wAA − wAa ) + pa (t)(wAa − waa )]
= . $;2'
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pA (t)2 wAA + pA (t) pa (t) wAa
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pA (t)2 + pA (t) pa (t)

5   
  

  
 
∆pA (t + 1) A

pA (t) (w̄A (t) − w̄(t))
∆pA (t + 1) = .
w̄(t)



 

 





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pA (∞)(wAA − wAa ) + (1 − pA (∞)) (wAa − waa ) = 0.
  
; 
 
 
 
  
46

1.0

h=0
0.8

− 0.5
h=−
0.6
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0.4
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0 200 400 600 800 1000

générations

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−waa + wAa 1 − sh − 1 + s
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1−h 1 + |h|
= = .
1 − 2h 1 + 2|h|
!  


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a   
 
   
∆ pA (∞) = 0
 
 
 
   
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M 
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a
  
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+ h = 0 
 
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aa  

 
A

wAA = wAa = 1
 waa = 1 − s.

! 


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pA (∞)2 + pA (∞) pa (∞) (1 − µ)
pA (∞) =
(pA (∞)2 + 2pA (∞)pa (∞) + pa (∞)2 (1 − s))
⇐⇒
 
pA (∞) pA (∞) + 2pA (∞)(1 − pA (∞)) + (1 − pA (∞))2 (1 − s) = (1−µ)pA (∞)
2

pA (∞)2 (1 − 2 + (1 − s)) + pA (∞)(2 − 2(1 − s)) + (1 − s) − (1 − µ) = 0


s(pA (∞))2 − 2s pA (∞) − µ + s = 0 ⇒ pa (∞) = µ/s.

+

 
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= .
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#

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1, 2, . . . , k 8 
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f1 , f2 , . . . , fk
m1 , m2 , . . . , mk = 1.

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i



  
 
 
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Y Lk ∈ R k×k

 

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⎜
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⎟.
⎝      ⎠
0 0 ··· 1 − mk−1 0
49 , 


! 



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n1 (t + 1) = f1 n1 (t) + · · · + fk nk (t)

 
 

 

#

 
   

ni (t) = (1 − mi−1 )ni−1 (t) (i = 2, . . . , k)

 


#

  
  
 


n(t) = Ltk n(0). $;6'

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:# 
f1 = f2 = 1
 m1 = 0'  

  



1 1
L2 =
1 0


 
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 n(0) = 10'  


  

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1 1 2 3 5
n(0) = ; n(1) = ; n(2) = ; n(3) = ; n(4) = ;...
0 1 1 2 3

8 


 

 
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1, 1, 2, 3, 5, 8, 13, . . . ,


  

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→ → → → → → ··· √ .
1 1 2 3 5 8 1+ 5
3
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n(t) = Lt2 n(0).


n(0)
  

 

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L2 n(0) = λ n(0),

 n(t) = λt n(0)# 
n(0) %

   

 
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1
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1, 618#
  
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4:

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$;6' 
 

 


 
Lk  !
 
  
 λ 
Lk 


(Lk − λ Ik ) = 0.
8 k = 1 L1 = f1
 λ = f1  8 k = 2

L2 =
f1
1 − m1
f2
0
,
 (f1 − λ)(−λ) − f2 (1 − m1 ) = 0.

5     
 

   

⎛ ⎞
f1 − λ f2 ··· fk−1 fk
⎜ 1 − m1 −λ ··· 0 0 ⎟
⎜
Lk − λ Ik = ⎜      ⎟
⎟.
⎝      ⎠
0 0 ··· 1 − mk−1 −λ
C 


 (Lk − λ Ik ) = −λ 
 (Lk−1 − λ Ik−1 ) −
⎛ ⎞
f1 − λ f2 · · · fk−2 fk
⎜ 1 − m1 −λ · · · 0 0 ⎟
(1 − mk−1 ) × 
 ⎜
⎜
     ⎟
⎟
⎝      ⎠
0 0 ··· 1 − mk−2 0
= −λ 
(Lk−1 − λ Ik−1 ) + (−1) (1 − mk−1 )(1 − mk−2 ) · · · (1 − m1 )fk .
k−1

   (  

(L1 − λ I1 ) = f1 − λ ! 

 

 
  

  
 

(L2 − λ I2 ) = −λ(f1 − λ) − (1 − m1 )f2 = λ2 − λ f1 − (1 − m1 )f2 .

G


(L3 − λ I3 ) = −λ(λ2 − λ f1 − (1 − m1 )f2 ) + (1 − m1 )(1 − m2 )f3
= −λ3 + λ2 f1 + λ(1 − m1 )f2 + (1 − m1 )(1 − m2 )f3 .
5   
 
  
 
  
λk − λk−1 f1 − λk−2 (1 − m1 )f2 − λk−3 (1 − m1 )(1 − m2 )f3 − · · ·
−(1 − m1 )(1 − m2 ) · · · (1 − mk−1 )fk . $;;'
!
 

  
 v = (v1 , . . . , vk )   
  
 < 
 λ v =
Lk v
  

λ v1 = f1 v1 + f2 v2 + · · · + fk vk
λ v2 = (1 − m1 )v1
λ v3 = (1 − m2 )v2


λ vk = (1 − mk−1 )vk−1 .
44 , 


!  

#


A
1 − m1
v2 = v1
λ
1 − m2 (1 − m1 )(1 − m2 )
v3 = v2 = v1
λ λ2


1 − mk−1 (1 − m1 )(1 − m2 ) · · · (1 − mk−1 )
vk = vk−1 = v1 .
λ λk−1
!
     
    
 
  

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(1 − m1 ) · · · (1 − mi )
  

   

(  

L
(i + 1)
M
  
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λ +

 
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k
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i=1

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∞
1= e−mx S(x) f (x)dx,
0

Y S(x)
    


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b
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+  
   
 
 
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= m × 8 (t),
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NA (t+
1)    
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NA (t + 1)|NA (t) ∼ D  (2N, pA (t)) , $;1'
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=3 , 


  

 

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   NA (t) 
#
A < 
 

E (NA (t + 1)|NA (t)) = 2N pA (t) = NA (t)
F (NA (t + 1)|NA (t)) = NA (t)(1 − pA (t)).
+ X
 Y   
 
 
 
 
   
 

E(X) = E (E (X|Y ))
F(X) = F (E (X|Y )) + E (F (X|Y )) .
5    

 
   
 NA (t + 1)
 NA (t)    
E(NA (t + 1)) = E (NA (t)) $;9'
F(NA (t + 1)) = F (NA (t)) + E (NA (t)(1 − pA (t))) . $;:'
! 



 



 

 

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#




 


E (NA (t)(1 − pA (t))) = N E (2pA (t)(1 − pA (t))) . $;4'

 


 

    pA (t) = 0  pA (t) = 1 !




 
  

H(t) = 2pA (t)(1 − pA (t)),


 
    

     
U#

  t + 1  
  
  



 


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a 5   
NA (t−1)   
  
 



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C 
E (H(t)) = E (E (2pA (t)(1 − pA (t))|NA (t − 1)))

 
  
 


 
U 
 
  

 

+ X ∼ D  (n, p)  
 

E(X(n − X)) = nE(X) − E(X 2 ) = nE(X) − (F(X) + E(X)2 )
= n2 p − (np(1 − p) + n2 p2 ) = (n2 − n)p(1 − p) = n(n − 1)p(1 − p).
  

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A
E (NA (t) (2N − NA (t))|NA (t − 1)) = 2N (2N − 1)pA (t − 1)(1 − pA (t − 1)).
5   
 
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 A

1
E (H(t)) = 1− E (H(t − 1)))
2N
 t  t
1 1
= 1− H(0) = 1− 2pA (0)(1 − pA (0)) . $;='
2N 2N
  
; 
 
 
 
  
=0

5     $;:'  
  

  


1
F(NA (t + 1)) = F (NA (t)) + 1 − 2N N E(H(t − 1))
 t
1
= F (NA (t)) + 1 − N 2pA (0)(1 − pA (0)).
2N

<


A

 t
1
F(NA (t + 1)) = F (NA (t)) + 1−
2N
N H(0)
 t−1  t 
1 1
= F (NA (t − 1)) + N H(0) 1− + 1−
2N 2N
 0  t 
1 1
= F (NA (0)) + N H(0) 1− + ··· + 1 −
2N 2N
1 − (1 − 1/(2N ))t+1
= 2N pA (0)(1 − pA (0)) .
1/(2N )

!  

 
 
  t = 0
  


 (2N )2 pA (0)−(2N )2 pA (0)2 





 

  
  



 
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t 
 
O


   


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! $;='  

U#

  

N 

 
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t → ∞
   
 


  



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O
 pA (t) → 0  
pA (t) → 1 


  

 
 


  


 
  
   
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A  

  

 
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(µs > µ)# 8


   


µ′ 





µ

µs ' µ < µd < µs # 8
 


µd − µ
0 ≤ h2 =
µs − µ
<1 $10'
  
1 !  
 
03=

faa(x)
fAA(x)
fAa(x)

partie
sélectionnée
f(x)

µaa µAa µ T µAA

valeur du caractère

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µaa = µ − m
µAA = µ∗ + m
µAa = µ∗ + d,
Y µ∗
 
  

 ± m
  V


U#
 d



U# C    


O
 G   #

⎧ ∗
⎨ µ + m,  AA
G= µ∗ + d,  Aa
µ − m,  aa.
⎩ ∗

!   

 


X  

10
 
 




5   m > 0   
 

 


a
  
 


A ! 
 µ∗  (µaa +µAa )/2
 




  

003 , 


fAA(x)

wAA − wAa~fAA(T) (m−d)

fAa(x)

T
valeur x du caractère

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fAA  fAa


 
 
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m/2
 
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A

∆pA = pA pa (pA (wAA − wAa ) + pa (wAa − waa ))/w̄.

< ∆pA
 
 
  


A  
 

 
+ # 


fAa (x) fAA (x)
 faa (x)   
 
 


 

 
 
  

O
 
  #
 (m, d)  

 


∞
∞
wAA − wAa = fAA (x)dx − fAa (x)dx
T T

∞
∞
≈ fAA (x)dx − fAA (x)dx
T T −d+m

T +m−d
= fAA (u)du ∼
= fAA (T ) · (m − d).
T


 

 
  


wAa − waa ∼
= fAA (T )(m + d),
  
1 !  
 
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∆pA ∼
= pA pa (pA fAA (T )(m − d) + pa fAA (T )(m + d))/w̄
∼
= pA pa fAA (T )(m + (pa − pA )d)/S.

! 
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w̄
  

 
      


  
    
   


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!
 

  
 
 
    

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 A
µd = (pA + ∆pA )2 µAA + 2(pA + ∆pA )(pa − ∆pA )µAa + (pa − ∆pA )2 µaa
= p2A (µ∗ + m) + 2pA ∆pA (µ∗ + m) + 2pA pa (µ∗ + d)
+2∆pA (pa − pA )(m∗ + d) + p2a (µ∗ − m) − 2pa ∆pA (µ∗ − m) + o(∆p2A )
≈ µ + 2∆pA (m + (pa − pA )d).

 
µ′ − µ ≈ 2∆pA (m + (pa − pA )d) = 2(m + (pa − pA )d)2 pA pa fAA (T )/S .

C
 



 

 
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f (x)
 

 

  
σ2    

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∞
∞
µs f (x)dx = x f (x)dx
 T   T

=S

∞ 
1 x−µ
= x ϕ dx
T σ σ

T −µ
= µS + ϕ σ
σ
  
≈ fAA (T )σ
1
=⇒ (µs − µ) = fAA (T )σ 2 .
S
B 

  
µ′ − µ 2pA pa (m + (pa − pA )d)2 2pA pa α2
h2 =
µs − µ
=
σ 2
=
σ2
. $12'
      
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α = m + (pa − pA )d,

 
 
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G
F(G) = E((G − µ∗ )2 ) − (E(G − µ∗ ))2
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= m2 (p2A + p2a ) − m2 ([pA − pa ][pA + pa ])2
= 2pA pa m2 ,

 pA + pa = 1 !
d = 0  
 


h2 = 0  F(G) = 0
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+   




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M
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B 
  
1 !  
 
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A B = α + β A !  
 
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E[(B − B)2 ]

  
  
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E (B = E (α + β A − B)2

= E (α + (βµA − µB ) + β {A − µA } − {B − µB })2
= (α + (βµA − µB ))2 + β 2 σA
2 2
+ σB − 2β (A, B).
5    
 
 

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α = µB − βµA
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!
 

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8  
 
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d = 0
  
  


 
F(G) = 2pA pa m2 + d2 (1 − 2pA pa ) − 2m d(pA − pa )

= 2pA pa α2 + 2pA pa d2

   
  


 
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= pa (m + d(pa − pA )) = pa α
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!
   
 
 



 
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−2d pA pa − 2pa α
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−(pa − pA )α
= 2pA pa d
aa µ∗ − m 5$,' −2pA α −m − m(pA − pa )
−2d pA pa + 2pA α
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8    I
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8

 

E(B) = E [E(G | 

) − E(G)] = E(G) − E(G) = 0
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5 
 
   

  
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(Gd , Gp ) = E (E [Gd − E(Gd )] [Gp − E(Gp )])
= E (E [Gd − E(Gd ) | Gp ] [Gp − E(Gp )])
= E (E (Bd + Id | Gp ) (Bp + Ip )) .
  
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(Gd , Gp ) = E (1/2 Bp (Bp + Ip ))
= 1/2 F(Bp ),

+ 
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d = E(Xp ) + (Xp − E(Xp )) (Xd , Xp ) .
X
F(Xp )
!





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(Gd , Gp ) = F(Bp )/2 = 1 h2 .
F(Xp ) F(Xp ) 2
(
 



     
 
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φuu = (1 + Fu )/2 ,

Y Fu
 

R
 
    
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1/2  


 
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(Gd1 , Gd2 ) 

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1.0
0.8
descendant
0.6

µ + (µS − µ)h2 2
0.4
0.2
0.0

0.0 0.2 0.4 0.6 0.8 1.0

un des parents

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1A
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5 
  




 

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(Bd1 , Bd2 |Gp1 , Gp2 ) = 2 × F(B)/4
8 





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F(I)/4 = 0
5     



O
  
 

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(Gu , Gv ) = 2 φuv F(B) + (φu v φu ′ ′ ′′ v ′′ + φu′ v′′ φu′′ v′ ) F(I).

  


 (u′ , u′′ )   
 
 
u
 (v′ , v′′ )   
 


v
  
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µ = 4pA
 
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Deuxième nucléotide du codon

U) C⎫ A G)
UUU Phe (F) UCU UAU ) Tyr (Y) UGU Cys (C)
UGC
⎪
U UUC UCC ⎪
⎬
Ser (S) UAC
UUA )
Leu (L) UCA ⎪ UAA ) STOP UGA -
STOP
UUG UCG ⎪
⎭
UAG UGG -
Trp (W)
CUU ⎫
⎪ CCU ⎫
⎪ CAU )
His (H) CGU ⎫
⎪
C CUC ⎪
⎬
Leu (L) CCC ⎪
⎬
Pro (P) CAC CGC ⎪
⎬
Arg (R)
CUA ⎪ CCA ⎪ CAA )
Gln (Q) CGA ⎪
CUG ⎪
⎭
CCG ⎪
⎭
CAG CGG ⎪
⎭

AUU ⎫
⎬ ACU ⎫
AAU )
Asn (N) AGU )
Ser (S)
AUC
⎪
A Leu (L) ACC ⎪
⎬
Thr (T) AAC AGC
AUA ⎭
ACA AAA )
Lys (K) AGA )
Arg (R)
AUG
⎪
-
Met (M) ACG ⎪
⎭
AAG AGG
GUU ⎫
⎪ GCU ⎫
⎪ GAU )
Asp (D) GGU ⎫
⎪
G GUC ⎪
⎬
Val (V) GCC ⎪
⎬
Ala (A) GAU GGC ⎪
⎬
Gly (G)
GUA ⎪ GCA ⎪ GAA )
Glu (E) GGA ⎪
GUG ⎪
⎭
GCG ⎪
⎭
GAG GGG ⎪
⎭




  
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